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Abstract

Background— Tecarfarin (ATI-5923) is a novel oral vitamin K antagonist. Unlike warfarin, it is metabolized by esterases, escaping metabolism by the cytochrome P450 system and thereby avoiding cytochrome P450–mediated drug-drug or drug-food interactions as well as genetic variations found in the cytochrome P450 system. Both tecarfarin and warfarin can be monitored with the international normalized ratio. We hypothesized that the time in therapeutic range for tecarfarin will exceed values usually experienced with warfarin.

Methods and Results— This was a 6- to 12-week open-label, multicenter, phase IIA study of 66 atrial fibrillation patients with a mild to moderate risk of stroke to determine the safety and tolerability of tecarfarin and to ascertain an optimal tecarfarin dosing regimen. Sixty-four subjects (97%) were taking warfarin at enrollment and were switched to tecarfarin. After the initial 3 weeks of tecarfarin treatment, the mean interpolated time in therapeutic range was 71.4%. Only 10.9% of patients had time in therapeutic range of <45%. Times in extreme international normalized ratio ranges of <1.5 and >4.0 were 1.2% and 1.2%, respectively. The median daily dose (for an individual patient) to maintain an international normalized ratio between 2 and 3 was 15.6 mg (range, 6 to 29 mg).

Conclusions— This is the first study of tecarfarin in patients with atrial fibrillation. It appears that tecarfarin may possess advantages over the currently available standard of care, warfarin, by improving time in therapeutic range. Adequately powered prospective trials are warranted to definitively compare tecarfarin with warfarin in clinical settings for which warfarin is indicated.

The number of dispensed warfarin prescriptions has been increasing, with nearly 31 million in the United States alone in 2004.1 Warfarin is highly efficacious but continues to pose significant management challenges.2–7 In well-conducted randomized controlled trials, time in therapeutic range (TTR) is usually only 60% to 65%.8–12 TTR is closely correlated with outcome, and improvements in TTR of as little as 10% convey a 29% improvement in all-cause mortality.13–16 Thus, achieving a higher TTR would achieve better outcomes.17

Several clinical and genetic factors are known to contribute to the variability seen with warfarin therapy. Warfarin is metabolized by multiple enzymes of the hepatic cytochrome P450 (CYP450) system, making it highly susceptible to drug-drug and drug-food interactions. It is also influenced by genetic variations of these enzymes.18–22 Genetic polymorphisms of the vitamin K epoxide reductase enzyme (VKORC1) contribute further to this variability.23–25 As a result, starting doses and variability in international normalized ratio (INR) values are not predictable.26

Tecarfarin is a novel oral vitamin K epoxide reductase (VKOR) antagonist with a mean terminal half-life of 119 hours (range, 107 to 140 hours). It is a structural analogue of warfarin, is highly protein bound (99%), and is metabolized by carboxylesterases in the hepatic microsomes, yielding a single inactive metabolite, ATI-5900. It has a mechanism of action identical to that of warfarin. A major point of differentiation from warfarin is that it is a single enantiomer and is not metabolized by the CYP450 system. It therefore offers the possibility of effective anticoagulation that can be monitored by INR analogous to warfarin but is expected to have fewer CYP450-mediated drug-drug and drug-food interactions. In this study, we therefore hypothesized that this will result in better control as determined by TTR, which in turn will lead to lower thromboembolic and hemorrhagic events. This is the first evaluation of tecarfarin in patients. The safety, tolerability, and efficacy of tecarfarin were assessed in this open-label, phase IIA study.

Methods

Study Design and Subjects

Tecarfarin-CLN-504 (ClinicalTrials.gov NCT00431782) was a multicenter, open-label, phase IIA study funded by ARYx Therapeutics, Inc, in patients with atrial fibrillation (AF). The primary objectives of the study were to determine the safety and tolerability of tecarfarin in patients with AF and to determine the optimal dosing regimen and INR monitoring schedule for tecarfarin that would attain and maintain INR in the accepted therapeutic range of 2.0 to 3.0. The study utilized subjects from 12 locations within the continental United States and was approved at all sites by institutional review boards.

Patients aged >18 years with AF documented by ECG at a low to moderate risk of stroke as assessed by a CHADS2 score of 0 to 2 and an indication for anticoagulation were eligible.27 The following patients were excluded: subjects with any history of ischemic or hemorrhagic stroke or transient ischemic attack, myocardial infarction, acute coronary syndrome, or coronary revascularization procedure within the prior 3 months; contraindications to anticoagulation (active bleeding, ulcerative lesions at risk of bleeding, about to undergo surgery or other invasive procedures such as lumbar puncture, blood dyscrasias or inherited disorders of hemostasis, history of hemorrhagic tendencies or prior serious hemorrhagic events such as hemorrhage within the cranium, eye, spinal cord, retroperitoneum, or gastrointestinal tract); concomitant therapy with antiplatelet agents other than aspirin 81 mg or treatment with any other investigational drug within 30 days of the study. In addition, subjects with hemoglobin <10 g/dL, platelet count <100 000/μL, or active liver or advanced kidney disease were excluded, as were women of child-bearing potential. All subjects were required to sign an institutional review board–approved written informed consent before enrollment.

Enrolled subjects received open-label, daily, evening tecarfarin for 6 weeks with the option of continuing therapy for an additional 6 weeks. For subjects not currently taking warfarin, the starting dose was 40 mg daily. This was based on earlier experience from studies in healthy volunteers. Subsequent dose adjustments as well as initial doses for subjects currently taking warfarin were based on INR and guided by a nomogram, which was modified twice during the conduct of the study to reflect ongoing dose titration experience (Table I in the online-only Data Supplement). CYP2C9 (*1/*2/*3) and VKORC1 (−1639 G/A) genotypes were determined at the first treatment visit.22,23 During the last half of the study, genotyping was done at the screening visit, and the VKORC1 genotype was used to prospectively adjust the starting dose for patients with the AA genotype. They were given a 10-mg starting dose rather than the 40-mg starting dose for patients with the GG and GA genotype. Only 3 of the 7 AA patients received a genotype-guided starting dose. Patients obtained INR measurements at least 3 times during the first week, twice during weeks 2 and 3 and once weekly during subsequent weeks. Levels of vitamin K1–dependent coagulation factors (II, VII, IX, X, proteins C and S) were also determined at screening and at weeks 6 and 12. Drug levels of tecarfarin were measured on days 5 and 12 and weeks 6 and 12. Dose titration was performed to achieve an INR of 2.0 to 3.0. Treatment compliance was determined as the percentage of the planned cumulative dose actually taken, based on tablet count.

At the end of the trial, patients were switched to warfarin. Tecarfarin is known to inhibit CYP2C9-mediated warfarin metabolism. The evidence is derived from transfected cells expressing individual CYP isoforms as well as from human liver microsomes. CYP2C9 was the only CYP isoform that was significantly inhibited by tecarfarin, with a Ki of 0.7±0.3 μmol/L. It was therefore possible that residual plasma concentrations of tecarfarin could inhibit warfarin metabolism and result in potentiation of warfarin effect. Therefore, patients were placed on half of their prestudy warfarin doses initially, and doses were adjusted incrementally on the basis of their INR. The warfarin-naive patients (n=2) were not of the AA genotype and were therefore placed on starting doses of 5 mg/d of warfarin and subsequently adjusted according to INR.

Statistical Analysis

There was no formal sample size determination. A target sample size of 40 to 60 was proposed. The evaluable population included all patients who received at least 1 dose of study medication. Two subjects with mitral valve replacements had a target INR range of 2.5 to 3.5. These 2 patients were excluded from the efficacy, but not safety, analyses. Patients with AF had a target INR range between 2.0 and 3.0.

TTR was determined by the linear interpolation method of Rosendaal et al28 and included all available (scheduled and unscheduled) INR values. In addition, a secondary analysis with the use of observed INR values was done. TTR was calculated after the first 3 weeks of dosing, the dose-finding period, was excluded. Poor control was defined as TTR <45% of target range.29 Linear regression analysis was performed to assess the effects of CYP2C9 and VKORC1 genotypes on TTR.

Attainment of a stable dose of tecarfarin was defined as 21 consecutive calendar days with all observed INR values within the therapeutic range. In addition, the weekly dose of tecarfarin was required to remain within a 20-mg range for each of the 3 weeks. Tecarfarin was supplied as 5-mg tablets. To administer an average daily dose of 17.5 mg, as an example, it was necessary to prescribe 15 mg alternating with 20 mg, resulting in a weekly dose of 120 mg alternating with 125 mg because of the odd number of days in the week. Thus, an additional requirement of the definition was that the weekly dose of tecarfarin had to remain within a 20-mg range for each of the 3 weeks. The average maintenance dose of tecarfarin was calculated as the mean daily dose during the period when the weekly INR was maintained within the therapeutic range. The Kruskal-Wallis test was used to compare the maintenance doses among CYP2C9 and VKORC1 genotypes.

Results

Patient Characteristics

Sixty-six patients received treatment; 59 completed 12 weeks of total therapy (Figure 1). Table 1 shows the demographics and baseline characteristics of the treated population. The majority of subjects (64/66; 97%) were receiving warfarin at enrollment. The overall allelic frequency distributions of CYP2C9 and VKORC1 polymorphism were similar to those in the reported literature (Table 1).30,31

Time in Therapeutic Range

After the initial 3 weeks of dose titration, the INR was within target range 71.4% of the time as measured by linear interpolation.29 After 1 week of treatment with tecarfarin, 77% of patients reached a therapeutic INR, and after 2 weeks of treatment, 95% of patients had attained a therapeutic INR (Table 2, Figure 2). TTR assessed with the use of observed INR values rather than interpolated INR values resulted in similar findings (Table 2). The proportion of patients with poorly controlled INR (<45% TTR) was 10.9% (with the use of weeks 4 to 12 INR values). The time spent significantly below therapeutic INR range (<1.5) was 1.2%; the time spent significantly above the therapeutic INR range (>4.0) was 1.2% (Table 2).

Coagulation Factors II, VII, IX, and X

All but 2 patients were being treated with warfarin at trial entry. The mean activity level of the coagulation factors was depressed at the screening visit and did not change dramatically during treatment with tecarfarin, although the variability (SD) decreased progressively. The mean activity levels for the 4 coagulation factors are summarized in Table 4. Figure 3 shows the relationship of activity of factor II to the INR as determined at the same visit. Generally, the activity of the coagulation factors decreases as the INR increases.

Pharmacokinetics of Tecarfarin

The mean plasma concentration of tecarfarin increased from day 5 to day 12 and then remained relatively constant (Figure 4). There was no evidence of accumulation of either tecarfarin or its major metabolite ATI-5900 after 12 weeks of dosing. There was variability of plasma concentrations between individuals. Plasma concentrations correlated with VKORC1 genotype, with the GG genotype having the highest concentrations (mean±SD of 10 591±3786 ng/mL on day 12), GA having an intermediate concentration (9229±3513 ng/mL), and AA having the lowest concentrations (4649±1036 ng/mL) (Figure 4). The maintenance dose was correlated with plasma concentration of tecarfarin (Figure 5). As expected, the lower dose required for the AA variants resulted in lower plasma concentrations. There was no relationship between plasma concentrations of tecarfarin and INR, even factoring in the VKORC1 genotype.

Discussion

This is the first study of tecarfarin in patients. It was administered for up to 12 weeks in patients with AF and was well tolerated without any clinically apparent toxicity or biochemical evidence of accumulation of the drug or its metabolite. The major finding was a TTR of 71.4% after exclusion of the first 3 weeks of therapy. This TTR compares favorably with TTR reported for warfarin in other trials and registries.8–17 For randomized controlled trials, the mean TTR reported in a systematic review was 67% (range, 44 to 73).15 In the present study, the mean TTR collected retrospectively, in an uncontrolled clinical setting from the patients entered in this study, over the year before enrollment was 59%. During the last 6 weeks of treatment, there was a trend toward improving TTR. The number of patients with poorly controlled anticoagulation (TTR <45%) was low, and the incidence of extreme INR values (<1.5 or >4.0) was also low. There is considerable evidence that clinical outcomes (ie, thromboembolism and major hemorrhage) are directly related to TTR and that an improved TTR leads to a reduction in the frequency of thromboembolic and hemorrhagic outcome events.14,28,32 A recent post hoc analysis of the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE-W) suggests that oral anticoagulation with low TTR was associated with poorer outcome compared with well-controlled patients with AF.33 This suggests that improvement in TTR with tecarfarin may subsequently result in improved thromboembolic and hemorrhagic event rates in patients requiring anticoagulation.13,34–36

Tecarfarin might provide a special advantage over warfarin in subjects with variant CYP2C9 genotypes because of the lack of CYP2C9-mediated drug-drug, drug-food, or other pharmacogenomic interactions. This population, in earlier studies with warfarin therapy, had exhibited lower TTR and higher supratherapeutic INR values and a greater propensity for hemorrhagic outcomes and are estimated to account for ≈15% of the variability in warfarin dosing.15,17–20,22,27,29,37 Tecarfarin does not appear to convey any special advantages over warfarin among subjects with variant VKORC1 polymorphisms consistent with its known mechanism of action as a VKOR inhibitor, which is shared with warfarin.15,17,19,22

Although genotype guidance was utilized for dose selection in this study, it was unlikely to have provided an advantage that translated into improved TTR for 2 reasons. First, gene testing was performed principally to identify the haplotype variants that would be prone to overanticoagulation and to confirm the hypothesis that variability in CYP2C9 genotypes would not affect dosing of tecarfarin. Only 3 of 7 patients with the sensitive AA VKORC1 genotype received genotype-guided initial dosing. Second, the recently conducted Couma-Gen study confirmed no added benefit of genotyping for either VKORC1 or CYP2C9 on TTR for warfarin, and therefore the likelihood of it benefiting TTR with tecarfarin is also unlikely.38 In this study, genotyping was used only for predicting initial dosing, and INR data for the first 3 weeks of the study were excluded, thus precluding any impact of genotyping on TTR at steady state dosing.

This study was the first study of tecarfarin in patients. It was limited by its open-label design, intensive monitoring, and lack of warfarin controls. Although this inhibits objective comparisons with current standard of care, there is compelling evidence from the literature that even controlled clinical trials involving warfarin have historically achieved TTR rates of 60% to 65%, and the 71.4% TTR achieved with tecarfarin as the first experience of the drug is promising. Additional clinical trials are needed to definitively compare tecarfarin with warfarin with the use of TTR and other clinical outcomes as end points.

Acknowledgments

Sources of Funding

Funding for this study was provided by ARYx Therapeutics Inc, Fremont, Calif.

Disclosures

Drs Ellis, Milner, and Canafax are employees of ARYx Therapeutics, Inc. Dr Ezekowitz serves as a consultant for ARYx Therapeutics, Inc, and has received grant support from ARYx Therapeutics, Inc. Dr Usman has no conflicts to declare.

CLINICAL PERSPECTIVE

This is the first evaluation of a novel vitamin K antagonist, tecarfarin (ATI-5923), in patients with atrial fibrillation. Tecarfarin is a structural analogue of warfarin that was designed to provide more uniform and stable anticoagulation. It is metabolized by carboxylesterases in the hepatic microsome and, unlike warfarin, circumvents the cytochrome P450 system isoenzyme CYP2C9, which is shared and influenced by many foods and drugs. The objective of this study is to prove that tecarfarin safely leads to a larger proportion of patients with a time in therapeutic international normalized ratio range of 2.0 to 3.0. Earlier studies have suggested that a greater time in therapeutic range with warfarin results in improved thromboembolic and hemorrhagic outcomes. This study finds that tecarfarin, by virtue of more stable metabolism, may be an easily regulated and efficacious anticoagulant. This study sets the stage for future direct comparisons between tecarfarin and warfarin with the use of time in therapeutic range as well as other end points. If tecarfarin is found to have greater time in therapeutic range than conventional warfarin therapy, it may prove to be an equally efficient and more easily regulated anticoagulant than warfarin.